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However, the absence of universal rules renders traditional screening methods time\u2010consuming and labor\u2010intensive, potentially leading to reduced or complete loss of activity. Here, we curated a D\u2010amino acid\u2010substituted AMP dataset from published literature and databases. We then developed ADAPT, an AI\u2010based tool for predicting the functional impact of D\u2010amino acid substitutions, and integrated it into a high\u2010throughput screening pipeline for AMP optimization. Of the variants obtained through this pipeline, 80% exhibited enhanced antibacterial activity. Among these, dR2\u20101 showed exceptional broad\u2010spectrum antimicrobial activity, reduced toxicity, and substantially improved stability. Mechanistic studies confirmed a membrane\u2010targeting antibacterial mode of action. Furthermore, we engineered a hydrogel delivery system that effectively treated cutaneous infections in mice. Overall, our study established an AI\u2010based framework for D\u2010amino acid substitution in AMPs, enabling the efficient discovery of potent and stable candidates with enhanced clinical translation\u00a0potential.<\/jats:p>","DOI":"10.1002\/advs.202518522","type":"journal-article","created":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T13:09:06Z","timestamp":1768396146000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["AI\u2010Based D\u2010Amino Acid Substitution for Optimizing Antimicrobial Peptides to Treat Multidrug\u2010Resistant Bacterial Infection"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-7550-9941","authenticated-orcid":false,"given":"Yinuo","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Gastroenterology Qilu Hospital of Shandong University Cheeloo College of Medicine, Shandong University Jinan 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